Drug development begins with the identification of a lead compound, based on the ability of the compound to exhibit a desired biological effect, such as the ability to inhibit bacterial growth, inhibit the activity of a target enzyme, increase or modulate the uptake of neurotransmitters, and the like. Biological activity is typically determined on the basis of in vitro experimentation or assays designed to rapidly identify candidate drugs. Typically, only a small percentage of the compounds tested will demonstrate sufficient activity and selectivity to merit further investigation.
Once a candidate or lead compound has been identified and selected for further development, its ADME/PK characteristics are determined. ADME/PK concerns the absorption, distribution, metabolism, excretion and pharmacokinetics of drugs in the body. The ADME/PK properties of a drug are critical, and often serve to distinguish pharmaceutical products from mere lead compounds. For example, a drug that is poorly absorbed orally may require intravenous (or other parenteral) administration to be effective, which may be unacceptable for the condition to be treated. A compound effective as an antibiotic may be ineffective to treat bacterial meningitis if its distribution does not carry it to the central nervous system. A compound that is rapidly metabolized and/or excreted may not reside in the body long enough to serve its intended purpose. These properties are all independent of the drug candidate's in vitro activity, and are difficult or impossible to predict based on current information. The complex factors that influence ADME/PK make it hard to model accurately, and necessitate the use of living tissues and research animals before a compound may proceed with clinical trials.
To enhance the speed of drug discovery and reduce the number of animals required, it is desirable to characterize the ADME/PK of mixtures of lead compounds (rather than single compounds) in procedures that involve either living animals (i.e., in vivo), or isolated organs or organ systems from animals.
In in vivo analyses of ADME/PK, plasma is generally the biophase used as the analytical endpoint. Measurement of individual drug candidates in plasma typically involves a unique extraction method based on the physicochemical properties of each molecule, in order to separate and quantify the compound from the numerous plasma components. Optimization of one plasma extraction method for all components of a chemical mixture poses a major problem for rapid screening.